The invention relates to new amidine derivatives, the preparation thereof using conventional methods and their use in pharmaceutical compositions.
The new amidine derivatives correspond to the formula 
wherein
R1 and R2, which may be identical or different, denote CF3, halogen, R5, OR5, COR6, SR6, SOR6, SO2R6, SO2NR5R7, C(OH)R5R7 or together may also denote the double-bonded groups xe2x80x94CR8xe2x95x90CR9xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CR8xe2x80x94CR9xe2x95x90CHxe2x80x94, xe2x80x94CR8xe2x95x90CHxe2x80x94CR9xe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94CHR10xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94(CH2)3-4xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94COxe2x80x94CH2CH2xe2x80x94Oxe2x80x94, linked with adjacent carbon atoms of the benzene ring, whilst these groups may in turn be substituted by C1-4-alkyl,
R3 denotes halogen, OH, CF3, R5, OR6, COR6, CONH5R7, CH2OH, CH2xe2x80x94Oxe2x80x94(C1-4-alkyl), SR6, SOR6, SO2R6, SO2NR5R7, NHxe2x80x94COxe2x80x94(C1-4-alkyl) , NHxe2x80x94SO2xe2x80x94(C1-4-alkyl), NR5R7 or C(OH)R5R7 (whilst if R3 is the same as R5, R5 can only denote H if at least one of the substituents R1 and R2 does not denote H), a heterocyclic 5-membered ring having 1 to 3 heteroatoms and of the formula 
xe2x80x83(wherein D, E and G, which may be identical or different, denote CH, N, Cxe2x80x94(C1-4-alkyl) or C-phenyl and L denotes O or S),
R4 denotes halogen, NH2, NHxe2x80x94(C1-4-alkyl), N(C1-4-alkyl)2, OH, C1-4-alkoxy,
R5 denotes H, C1-12-alkyl, phenyl, phenyl optionally substituted by halogen, C1-4-alkyl, C1-4-alkoxy or C2-5-acyl, or phenyl-(C1-4-alkyl),
R6 denotes C1-12-alkyl, phenyl, or phenyl optionally substituted by halogen, C1-4-alkyl, C1-4-alkoxy or C2-C5-acyl,
R7 denotes H or C1-2-alkyl,
R8, R9 (which may be identical or different) denote H, OH, C1-4-alkyl, C1-4-alkoxy or C2-5-acyl,
R10 denotes H or C1-4-alkyl,
R11, R12, which may be identical or different, denote H, OH, halogen, CF3, C1-4-alkyl or C1-4-alkoxy,
A denotes one of the groups 
B denotes CHxe2x95x90CH, CHxe2x95x90N, S or 
A1 denotes C2-4-alkylene, cis- or trans-CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2, CH2xe2x80x94Cxe2x80x94Cxe2x89xa1CH2 or 
A2 denotes C1-5-alkylene,
X1 denotes O, NH, S, SO, SO2, CO, CH2 or 
X2 denotes O, NH, S or 
X3 denotes NHxe2x80x94CO, COxe2x80x94NH, SO2xe2x80x94NH or 
X4 denotes NHxe2x80x94CO, COxe2x80x94NH, NHxe2x80x94SO2, SO2xe2x80x94NH or, NHxe2x80x94COxe2x80x94NH,
and (if they contain one or more chiral centres), may occur in the form of racemates, in enantiomerically pure or concentrated form, possibly as pairs of diastereomers and (if a double bond is present) in cis- or trans-form and as free bases or as salts, preferably with physiologically acceptable acids.
Within the scope of the above definitions, the preferred compounds are the compounds of formula 
wherein
R1, R2, which may be identical or different, denote R7, OR7, COR6, halogen or together denote the double bonded groups xe2x80x94CR8xe2x95x90R9xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CR8xe2x80x94CR9xe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94CHR10xe2x80x94CH2xe2x80x94 or xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, linked with adjacent carbon atoms of the benzene ring,
R3 denotes halogen, CF3, R7, OR7, COxe2x80x94(C1-4-alkyl), NHxe2x80x94COxe2x80x94(C1-4-alkyl), NHSO2xe2x80x94(C1-4-alkyl) or N(R10)2 (whilst R7 can only denote H if at least one of the substituents R1 and R2 does not denote H) or a heterocyclic five-membered ring such as 
R6 and R7 are as hereinbefore defined, and
A denotes the group II.
The following may be particularly mentioned as examples of the group of formula xe2x80x94C6H2R1R2R3: 
Of the definitions of A particular mention may be made of: 
Special mention should also be made of the compounds of formula 
wherein
a denotes 0 or 1,
b denotes 1 or 2,
R denotes C1-4-alkyl, and if a=0 or 1 and b=1, and if a=1 and b=2, R may also denote hydrogen, and
R preferably denotes CH3, C2H5 or H, and for a=1, b is preferably 1.
In the above definitions, the term halogen denotes F, Cl, Br or I, preferably F, Cl. If the groups listed are alkyl chains or contain alkyl chains, these may be straight-chained or branched. The alkyl chains in R5, R6 and R7 preferably contain up to 6 carbon atoms, more particularly 1 to 4 carbon atoms. In particular, as a constituent of COR6, R6 denoting alkyl may also be mono- or poly-fluorine-substituted. Particular examples of substituents of ring systems are alkyls such as methyl, ethyl and the propyl. A preferred acyl group is COCH3, a preferred alkoxy group is CH3O. The bridged A preferably contains 4 to 6 members. The group is arranged between the two ring systems in formula I and in corresponding formulae so as to correspond to the written form of formulae II to VI, whereas the groups which are valid for both R1 and R2 are not listed in the proper orientation. If R1 and R2 together denote a double bonded group, R3 preferably denotes H or C2-5-acyl, e.g. acetyl. The groups R1, R2 and R3 should not all simultaneously denote CF3, COR6, SR6, SOR6, SO2R6, SO2NR5R7 or C(OH)R5R7, but rather these groups as well as OR5, with the definition phenoxy or substituted phenoxy, preferably occur only once or possibly twice, whilst alkyl, acyl and halogen, in particular, may occur as further substituents. The bonds or CH2groups in IX/IXa/IXb are generally in the xcex1-position to one another. Typical groups for A are, for example, Oxe2x80x94(CH2)2xe2x80x94O, Oxe2x80x94(CH2)4xe2x80x94O, whilst one of the O-atoms may be replaced by S, NH or CO, as well as groups such as CH2xe2x80x94CH2xe2x80x94CONH, CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CO, COxe2x80x94NHxe2x80x94CH2xe2x80x94CH2 or NHxe2x80x94COxe2x80x94CH2xe2x80x94CH2. The amidino group is usually in the para-position relative to the carbon atom to which A is linked.
The new compounds are prepared by conventional methods.
1. Reaction of imidoesters of the formula 
wherein R1 to R4, A and B are as hereinbefore defined and R preferably represents a C1-6-alkyl group or benzyl (but if desired the man skilled in the art can also use derivatives of other alcohols), and ammonia. The reaction is preferably carried out in an organic solvent at temperatures between about 0xc2x0 C. and the boiling temperature of the reaction mixture, preferably between ambient temperature and about 100xc2x0 C. or the boiling temperature, if this is lower. Suitable solvents are polar solvents such as methanol, ethanol and propanol.
If the starting materials are sufficiently acid-resistant the reaction may be carried out via the corresponding acid imide chlorides instead of the imidoesters.
2. In order to prepare compounds of formula I wherein A is linked via O or S to at least one of the ring systems:
Reaction
(a) of a phenol or thiophenol of formula 
xe2x80x83wherein Z denotes OH or SH and R1, R2 and R3 are as hereinbefore defined, with a compound of the formula 
xe2x80x83wherein A1, A2, B, R4, X2 and X3 are as hereinbefore defined and L represents a nucleofugic leaving group, or
(b) of a phenol or thiophenol of the formula 
xe2x80x83wherein B, R4 and Z are as hereinbefore defined, with a compound of the formula 
xe2x80x83wherein A1, A2, R1, R2, R3 and Z are as hereinbefore defined.
The reaction is carried out in aprotic solvents such as dimethylsulphoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol with the addition of a basel(metal carbonates, metal hydroxides, metal hydrides) at temperatures between about 0 and 140xc2x0 C. or the boiling temperature of the reaction mixture.
The phenols or thiophenols may also be used in the form of salts, e.g. alkali metal salts. Examples of suitable nucleofugic leaving groups include halogens such as Br and Cl.
3. Reduction of an amidoxime of the formula 
wherein A, B and R1 to R4 are as hereinbefore defined.
For the reduction of XIX it is appropriate to use catalytic hydrogenation, particularly with Raney nickel in a lower alcohol such as methanol. Conveniently, the amidoxime of formula XIX is dissolved in methanol, with the addition of the calculated amount of the particular acid the salt of which is the desired end product, and hydrogenated at ambient temperature under gentle pressure, e.g. up to 5 bar, until the uptake of hydrogen has ended.
The starting materials may be obtained from known compounds by conventional methods.
Thus, the starting materials for process 1 may be obtained from the corresponding nitrites by reacting them with HCl via the step of the imide chlorides or directly by reacting them with, for example, C1-6-alcohols or benzyl alcohol in the presence of an acid such as HCl. The reaction of the nitrites with H2S in solvents such as pyridine or dimethylformamide in the presence of a base such as triethylamine and subsequent alkylation or benzylation result in compounds of formula X. Starting from carboxylic acid amides, which moreover correspond to the compounds of formula X, compounds of formula X may also be obtained by reaction with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate, in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 0 and 50xc2x0 C., preferably at ambient temperature.
The starting materials XIX may also be obtained by reacting corresponding amidoximes instead of amidine analogously to method 1 or 2; by analogous reaction of corresponding nitriles from which the starting materials XIX are finally obtained by the addition of hydroxylamine.
The compounds according to the invention are therapeutically useful, particularly in the light of their LTB4-antagonistic activity. They are therefore suitable for use, particularly, in those diseases in which inflammatory and/or allergic processes are involved, such as asthma, ulcerative colitis, psoriasis and also for treating gastropathy induced by non-steroidal antiphlogistics. The new compounds may also be used in conjunction with other active substances, e.g. antiallergics, secretolytics, xcex22-adrenergics, steroids for inhalation, antihistamines and/or PAF-antagonists. They may be administered by topical, oral, transdermal, nasal or parenteral route or by inhalation.
The therapeutic or prophylactic dose is dependent on the nature and gravity of the disease, as well as the potency of the individual compounds and the body weight of the patient. For oral administration the dose is between 10 and 250 mg, preferably between 20 and 200 mg. For inhalation, the patient takes between about 2 and 20 mg of active substance. The new compounds may be administered in conventional preparations such as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments and suppositories.
The Examples which follow illustrate some possible formulations for the preparations.
Formulation Examples
1. Tablets
The constituents are processed in the usual way to form tablets weighing 500 mg. If desired, the content of active substance may be increased or reduced and the quantity of dextrose reduced or increased accordingly.
2. Suppositories
The ingredients are processed in the usual way to form suppositories weighing 1.7 g.
3. Powder for Inhalation
Micronised powdered active substance (compound of formula I; particle size about 0.5 to 7 xcexcm) is packed into hard gelatine capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled using conventional inhalation devices, e.g. according to DE-A 3 345 722.
The compounds according to the invention were tested inter alia for their activity in the tests described below.
a) U937xe2x80x94Receptor Binding Test/LTB4 
The binding of 3H-LTB4 (3 nM) to vital U937 cells (differentiated human monocytary cell line with naturally expressed LTB4 receptors) is inhibited, in dosage dependent manner, by an increasing concentration of the test substance (incubation 2 hours at 0xc2x0C.). After the unbound 3H-LTB4 has been separated off by membrane filtration, the radioactivity of the bound LTB4 receptor/3H-LTB4 complex is quantified by scintillation measurement. The affinity (inhibition constant Kj) was determined by repeated adaptation of a displacement curve to the measurements (program: xe2x80x9ccoupled mass equilibriaxe2x80x9d on Wang computer).
b) Aggregation of Neutrophilic Granulocytes in the Guinea-pig
Indicated by LTB4 in vitro (increase in light transmission in the aggregometer, recorded in mm; each experiment repeated twice): inhibition 2 minutes after incubation with test substance in polydiol/DMSO.
c) Leukotrien-B4-indicated Accumulation of Neutrophiles in the Mouse Ear
Evaluation of the neutrophilic influx by photometric measurement (mOD/min) of the myeloperoxidase activity (Bradley et al.: J. Invest. Dermatol. 78, 206, 1982) in the skin of the ear. Increase 6 hours after topical treatment of the left ear with LTB4 (250 ng on each side) compared with the right ear (2xc3x975 xcexcl acetone as solvent).
Substance administered by oral route in 1% tylose 300, 30 minutes before the LTB4 stimularion.
4. Results
The 3H-LTB4-receptor binding to guinea-pig spleen cells in the presence of 10% blood plasma yielded Kj-values of, in some cases, far less than 1 xcexcM, more particularly between 0.2 and 0.02. Inhibition of the LTB4-induced aggregation of neutrophiles resulted in EC50-values between about 0.5 and 0.05 xcexcM.
Particular mention should be made of the compounds according to Examples 1 and 5 and Nos. 10, 11, 13, 19, 20, 22 and 23 from Table I, No. 1 from Table II, No. 2 from Table III.
The Examples which follow illustrate the possible methods of preparing the compounds according to the invention.
Process 1